Use of anthracyclinone derivatives in amyloidosis

ABSTRACT

PCT No. PCT/EP95/02928 Sec. 371 Date Apr. 4, 1996 Sec. 102(e) Date Apr. 4, 1996 PCT Filed Jul. 24, 1995 PCT Pub. No. WO96/04895 PCT Pub. Date Feb. 22, 1996The present invention provides the new use in the treatment of amyloidosis with the anthracyclinone of formula (A) wherein R1, R2, R3, R4, and R5, are appropriate substituents. Some compounds of formula (A) are novel. Processes for their preparation and pharmaceutical composition containing them are also described.

This application is a 371 of PCT/EP95/02928 filed Jul. 24, 1995.

The present invention relates to treating amyloidosis, to novelcompounds for such treatment, to processes for their preparation and topharmaceutical compositions containing them.

The relationship between amyloidosis, cell death and loss of tissuefunction appears to be of relevance for different types of disordersincluding neurodegenerative disorders. Therefore, the prevention ofamyloid formation and/or the induction of amyloid degradation can be animportant therapeutic tool for all pathological disorders associatedwith amyloidosis including AL amyloidosis and neurodegenerativedisorders of the Alzheimer's type.

More particularly, the present invention provides the use in themanufacture of a medicament for use in the treatment of amyloidosis ofan anthracyclinone of formula A ##STR1## wherein R₁ represents:

hydrogen or hydroxy;

a group of formula OR₆ in which R₆ is C₁ -C₆ alkyl, C₅₋₆ cycloalkyl orCH₂ Ph with the phenyl (Ph) ring optionally substituted by 1, 2 or 3substituents selected from F, Cl, Br, C₁ -C₆ alkyl, C₁ -C₆ alkoxy andCF₃ ; or

a group of formula OSO₂ R₇ in which R₇ is C₁ -C₆ alkyl or Ph optionallysubstituted by 1, 2 or 3 substituents selected from halogen, such as F,Cl or Br, and C₁ -C₆ alkyl;

R₂ represents hydrogen, hydroxy, OR₆, COOH or COOR₆ wherein R₆ is asabove defined;

R₃ represents hydrogen, hydroxy or OR₆ as above defined;

R₄ represents hydrogen, methyl or a group of formula XCH₂ R₈ in which Xis CO, CH₂, CHOH or a group of formula ##STR2## in which m is 2 or 3 andR₈ is: hydrogen or hydroxy;

a group of formula NR₉ R₁₀ in which:

R₉ and R₁₀ are each independently selected from:

(a) hydrogen,

(b) a C₁ -C₆ alkyl or C₂ -C₆ alkenyl group optionally substituted withhydroxy, CN, COR₁₁, COOR₁₁, CONR₁₁ R₁₂, O(CH₂)_(n) NR₁₁ R₁₂ (n is 2 to4) or NR₁₁ R₁₂ in which R₁₁ and R₁₂ are each independently selected fromhydrogen, a C₁ -C₁₂ alkyl or C₂ -C₁₂ alkenyl group or phenyl optionallysubstituted by one or more, for example 1, 2 or 3, substituents selectedfrom C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃, OH, NH₂ or CN,

(c) C₃₋₆ cycloalkyl optionally substituted with COR₁₁, COO₁₁ or OHwherein R₁₁ is as above defined,

(d) phenyl(C₁ -C₄ alkyl or C₁ -C₄ alkenyl) optionally substituted on thephenyl ring by one or more, for example 1, 2 or 3, substituents selectedfrom C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃, OH, NH₂ or CN, or

(e) COR₁₁, COOR₁₁, CONR₁₁ R₁₂, COCH₂ NR₁₁ R₁₂, CONR₁₁ COOR₁₂ or SO₂ R₁₂in which R₁₁ and R₁₂ are as above defined, or

R₉ and R₁₀ together with the nitrogen atom to which they are attachedform:

(f) a morpholino ring optionally substituted with C₁ -C₄ alkyl or C₁ -C₄alkoxy,

(g) a piperazino ring optionally substituted by C₁ -C₆ alkyl, C₂ -C₆alkenyl or phenyl optionally substituted by one or more, for example 1,2 or 3, substituents selected from C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br,Cl, CF₃, OH, NH₂ or CN, or

(h) a pyrrolidino or piperidino, or tetrahydropyridino ring optionallysubstituted by OH, NH₂, COOH, COOR₁₁, or CONR₁₁ R₁₂ wherein R₁₁ and R₁₂are as above defined, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or phenyl optionallysubstituted by one or more, for example 1, 2 or 3, substituents selectedfrom C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃, OH, NH₂ or CN;

a group of formula OR₆ or SR₆ in which R₆ is as above defined;

a group of formula O-Ph wherein the phenyl (Ph) ring is optionallysubstituted by nitro, amino or NR₉ R₁₀ as above defined;

a group of formula B ##STR3## wherein R₁₃ represents hydrogen, COR₁₁wherein R₁₁ is as above defined, or a peptidyl residue and R₁₄ ishalogen or a group of formula OSO₂ R₇ wherein R₇ is as above defined; or

a group of formula C or D: ##STR4## wherein E is a group of formulaCOOR₁₁ or CONR₉ R₁₀ in which R₉, R₁₀ and R₁₁ are as above defined; and

R₅ represents hydrogen, hydroxy, a group of formula OR₆ or NR₉ R₁₀wherein R₆, R₉ and R₁₀ are as above defined, or a group of formula E:##STR5## wherein R₆, R₉ and R₁₀ are as above defined and p is from 1 to6; and the pharmaceutically acceptable salts thereof.

In a further aspect of the present invention there are provided novelanthracyclinones of the formula A as above defined, with the followingprovisos:

R₅ does not represent NR₉ R₁₀ wherein R₉ and R₁₀ are as above definedunder a) to c) or e) to h) when R₁ is H, OH or OCH₃, R₂ is H, R₃ is OHand R₄ is a group of formula XCH₂ OH or XCH₃ wherein X is as abovedefined;

R₅ does not represent H or OH when R₁ is H, OH or OCH₃, R₂ is H, OH,COOCH₃ and R₄ is a group of the formula, XCH₃ or XCH₂ OH, wherein X isas above defined;

R₄ does not represents COCH₂ OR'₆ wherein R'₆ is phenyl, benzyl, C₁ -C₆alkyl or C₅ -C₆ cycloalkyl when R₁ is H or OH, R₅ and R₄ are OH and R₂is H;

the compound of formula A is not one of the following derivatives:

14-(N-morpholino)-daunomycinone;

14-(N-piperidino)-daunomycinone;

14-acetamido-daunomycinone;

14-acetamido-4-demethoxy daunomycinone;

14-(N-morpholino)-carminomycinone;

14-(N-methyl-N-piperazino)-daunomycinone;

14-(N-morpholino)carminomycinone;

14-(N-methyl-N-piperazine) carminomycinone.

Each alkyl, alkoxy or alkenyl group may be a straight chain or branchedchain group.

A C₁ -C₁₂ alkyl group is preferably a C₁ -C₆ alkyl, more preferably a C₁-C₄ alkyl group. A C₁ -C₆ alkyl group is preferably a C₁ -C₄ alkylgroup. A C₁ -C₆ alkyl group is preferably methyl, ethyl, n-propyl,iso-propyl, n-butyl, t-butyl, sec-butyl or n-pentyl. A C₁ -C₄ alkylgroup is preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl,t-butyl or sec-butyl.

A C₃ -C₆ cycloalkyl group is preferably a C₅₋₆ cycloalkyl group. A C₅₋₆cycloalkyl group is preferably cyclopentyl or cyclohexyl.

A C₂ -C₁₂ alkenyl group is preferably a C₂ -C₆ alkenyl group, morepreferably a C₂ -C₄ alkenyl group. A C₂ -C₆ alkenyl group is preferablya C₂ -C₄ alkenyl group. Preferred alkenyl groups are ethenyl andpropenyl.

A peptidyl residue may comprise up to 6, for example 1 to 4, amino acidresidues. Suitable peptide residues are selected from Gly, Ala, Phe,Leu, Gly-Phe, Leu-Gly, Val-Ala, Phe-Ala, Leu-Phe, Phe-Leu-Gly,Phe-Phe-Leu, Leu-Leu-Gly, Phe-Tyr-Ala, Phe-Gly-Phe, Phe-Leu-Gly-Phe,Gly-Phe-Leu-Gly, Gly-Phe-Leu-Gly.

In the present, R₁ is preferably hydrogen or methoxy. R₂ is preferablyhydrogen. R₃ is preferably hydroxy. R₄ is preferably a group of formulaXCH₂ R₈ in which X is CO, CH₂ or a group of formula: ##STR6## and R₈ ishydrogen, a group of formula NR₉ R₁₀, a group of formula O-Ph whereinthe Ph ring is optionally substituted by NR₉ R₁₀, a group of formula Bor a group of formula C wherein R₉ and R₁₀ are each independentlyselected from:

(a') hydrogen,

(b') C₁ -C₄ alkyl optionally substituted by O(CH₂)_(n) NR₁₁ R₁₂ or NR₁₁R₁₂ wherein n, R₁₁ and R₁₂ are as above defined,

(d') benzyl optionally substituted on the phenyl ring by one or more,for example 1, 2 or 3, substituents selected from C₁ -C₄ alkyl, C₁ -C₄alkoxy, F, Br, Cl, CF₃, OH, NH₂ or CN, or

(e') COCF₃ or COCH₂ NR₁₁ R₁₂ wherein R₁₁ and R₁₂ are as above defined,

or R₉ and R₁₀ together with the nitrogen atom to which they are attachedform:

(f') a morpholino ring,

(g') a piperazino ring optionally substituted by C₁ -C₄ alkyl, or

(h') a pyrrolidino or piperidino ring, or tetrahydropyridino,

R₁₃ in the group of formula B is hydrogen, R₁₄ in the group of formula Bis I or OSO₂ (C₁ -C₄ alkyl) and E in the group of formula C is a groupof formula CONR'₉ R'₁₀ wherein R'₉ and R'₁₀ together with the nitrogenatom to which they are attached form a piperazino ring optionallysubstituted by C₁ -C₄ alkyl. More preferably R₄ is a group of formula##STR7## or a group of formula XCH₂ R₈ wherein X is CO or CH₂ and R₈ ishydrogen, a group of formula NR₉ R₁₀, a group of formula O-Ph whereinthe Ph ring is optionally substituted by NH₂ or NHCOCH₂ N(C₁ -C₄alkyl)₂, a group of formula B or a group of formula C wherein R₉ and R₁₀are each independently selected from:

(a") hydrogen,

(b") a methyl or ethyl group optionally substituted by O(CH₂)_(n) NH₂ orNH₂ wherein n is as above defined,

(d") benzyl optionally substituted on the phenyl ring by 1, 2 or 3substituents selected from C₁ -C₄ alkyl and C₁ -C₄ alkoxy, or

(e") COCF₃ or COCH₂ N(C₁ -C₄ alkyl)₂, or R₉ and R₁₀ together with thenitrogen atom to which they are attached form:

(f") a morpholino ring,

(g") a piperazino ring optionally substituted by C₁ -C₄ alkyl, or

(h") a pyrrolidino, piperidino or 1,2,3,6 tetrahydropyridino ring,

R₁₃ in the group of formula B is hydrogen, R₁₄ in the group of formula Cis I or OSO₂ (C₁ -C₄ alkyl) and E in the group of formula C is a groupof formula CONR'₉ R'₁₀ wherein R'₉ and R'₁₀ together with the nitrogenatom to which they are attached form a piperazino ring optionallysubstituted by C₁ -C₄ alkyl.

R₅ is preferably hydrogen, hydroxy or a group of formula NR₉ R₁₀ asabove defined.

The present invention provides the salts of those compounds of formula Athat have salt-forming groups, especially the salts of the compoundshaving a carboxylic group, a basic group (e.g. an amino group); thesalts are especially physiologically tolerable salt, for example alkalimetal and alkaline earth metal salts (e.g. sodium, potassium, lithium,calcium and magnesium salts), ammonium salts, salts with an appropriateorganic amine or amino acid (e.g. arginine, procaine salts) and theaddition salts formed with suitable organic or inorganic acids, forexample hydrochloric acid, sulfuric acid, carboxylic acid and sulfonicorganic acids (e.g. acetic, trifluoroacetic, p-toluensulphonic acid).

The present invention encompasses all the possible stereoisomers as wellas their racemic or optically active mixtures. Preferably R₃ is in theα-configuration, i.e. below the plane of the ring.

Specific examples of the preferred compounds for the use of the presentinvention are those listed hereinunder:

    ______________________________________                                        A1:  14-(N-morpholino)-daunomycinone                                                ##STR8##                                                                A2:  14-(N-piperidino)-daunomycinone                                                ##STR9##                                                                A3:  14-(N-pyrrolidino)-daunomycinone                                               ##STR10##                                                               A4:  14- N-(N'-methyl)-piperazino!-daunomycinone                                    ##STR11##                                                               A5:  14-(3',4'-dimethoxybenzylamino)!-duanomycinone                                R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 =OH,                      R.sub.4 = COCH.sub.2 NHCH.sub.2  C.sub.6 H.sub.3 (OCH.sub.3).sub.2            !                                                                        A6:  14-aminoethyloxyethylamino-daunomycinone                                      R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 =OH,                      R.sub.4 = COCH.sub.2 NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NH.sub.2       A7:  14-aminoethylamino-daunomycinone                                              R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.4 =           COCH.sub.2 NH(CH.sub.2).sub.2 NH.sub.2                                   A8:  14-(N-aminoethyl-N-trifluoroacetylamino)-                                     daunomycinone                                                                 R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH,                     R.sub.4 = COCH.sub.2 N(COCF.sub.3)(CH.sub.2).sub.2 NH.sub.2              A9:  14-(N-aminoethyloxyethyl-N-trifluoroacetylamino)-                             daunomycinone                                                                 R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.4 = COCH.sub.2 N(COCF.sub.3)(         CH.sub.2).sub.2 O(CH.sub.2).sub.2 NH.sub.2,                                   R.sub.3 = R.sub.5 = OH                                                   A10: 4-demethoxy-14-(N-morpholino)-daunomycinone                                    ##STR12##                                                               A11: 4-demethoxy-14-(N-piperidino)-daunomycinone                                    ##STR13##                                                               A12: 4-demethoxy-14-(N-pyrrolidino)-daunomycinone                                   ##STR14##                                                               A13: 4-demethoxy-14-N- (N'-methyl)-piperazino!-                                    daunomycinone                                                                  ##STR15##                                                               A14: 4-demethoxy-14-(3',4'-dimethoxybenzylamino)                                   daunomycinone                                                                 R.sub.1 = R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.4 = COCH.sub.2           NHCH.sub.2  C.sub.6 H.sub.3 (OCH.sub.).sub.2 !                           A15: 4-demethoxy-14-aminoethyloxyethylamino-daunomycinone                          R.sub.1 = R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.4 = COCH.sub.2           NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NH.sub.2                            A16: 4-demethoxy-14-(n-aminoethyloxyethyl-N-                                       trifluoroacetylamino)-daunomycinone                                           R.sub.1 = R.sub.2 = H, R.sub.3 = R.sub.5 = OH,                                R.sub.4 = COCH.sub.2 N(COCF.sub.3)(CH.sub.2).sub.2 O(CH.sub.2).sub.2          NH.sub.2                                                                 A17: 7-deoxy-14-(N-morpholino)-daunomycinone                                        ##STR16##                                                               A18: 7-deoxy-14-(N-piperidino)-daunomycinone                                        ##STR17##                                                               A19: 7-deoxy-14-(N-pyrrolidino)-daunomycinone                                       ##STR18##                                                               A20: 7-deoxy-14- N-(N'-methyl)-piperazino!-daunomycinone                            ##STR19##                                                               A21: 7-deoxy-14-(3',4'-dimethoxybenzylamino)-daunomycinone                         R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                     R.sub.4 = COCH.sub.2 NHCH.sub.2  C.sub.6 H.sub.3 (OCH.sub.3).sub.2            !                                                                        A22: 7-deoxy-14-aminoethyloxyethylamino-daunomycinone                              R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                     R.sub.4 = COCH.sub.2 NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NH.sub.2       A23: 7-deoxy-14-(N-aminoethyloxyethyl-N-                                           trifluoroacetylamino)-daunomycinone                                           R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                     R.sub.4 = COCH.sub.2 N(COCF.sub.3)(CH.sub.2).sub.2 O(CH.sub.2).sub.2          NH.sub.2                                                                 A24: 4-demethoxy-7-deoxy-14-(N-morpholino)-daunomycinone                            ##STR20##                                                               A25: 4-demethoxy-7-deoxy-14-(N-piperidino)-daunomycinone                            ##STR21##                                                               A26: 4-demethoxy-7-deoxy-14-(N-pyrrolidino)-daunomycinone                           ##STR22##                                                               A27: 4-demethoxy-7-deoxy-14- N-(N'-methyl)-piperazino!-                            daunomycinone                                                                  ##STR23##                                                               A28: 4-demethoxy-7-deoxy-14-(3',4'-dimethoxybenzylamino)-                          daunomycinone                                                                 R.sub.1 = R.sub.2 = R.sub.5 = H, R.sub.3 = OH, R.sub.4 = COCH.sub.2           NHCH.sub.2  C.sub.6 H.sub.3 (OCH.sub.3).sub.2 !                          A29: 4-demethoxy-7-deoxy-14-aminoethyloxyethylamino-                               daunomycinone                                                                 R.sub.1 = R.sub.2 = R.sub.5 = H, R.sub.3 = OH, R.sub.4 = COCH.sub.2           NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NH.sub.2                            A30: 7-deoxy-7-(N-morpholino)-daunomycinone                                         ##STR24##                                                               A31: 7-deoxy-7- bis(2'-hydroxyethyl)!amino-daunomycinone                           R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = COCH.sub.3, R.sub.5 = N(CH.sub.2 CH.sub.2 OH).sub.2                    A32: 7-deoxy-7-(3',4'-dimethoxybenzylamino)!-13-deoxo-13-                          ethylene-dioxy-daunomycinone                                                  R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = C(OCH.sub.2 CH.sub.2 O)CH.sub.3,                                            R.sub.5 = NHCH.sub.2 C.sub.6 H.sub.3 (OCH.sub.3).sub.2                   A33: 7-deoxy-7-benzylamino-13-deoxo-13-ethylenedioxy-                              daunomycinone                                                                 R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = C(OCH.sub.2 CH.sub.2 O)CH.sub.3,                                            R.sub.5 = NHCH.sub.2 C.sub.6 H.sub.5                                     A34: 7-deoxy-7-(2'-hydroxyethylamino)-13-deoxo-13-                                 ethylenedioxy-daunomycinone                                                   R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = C(OCH.sub.2 CH.sub.2 O)CH.sub.3,                                            R.sub.5 = NHCH.sub.2 CH.sub.2 OH                                         A35: 4-demethoxy-7-deoxy-7-(3',4'-dimethoxybenzylamino)-                           13-deoxo-13-ethylenedioxy-daunomycinone                                       R.sub.1 = R.sub.2 = H, R.sub.3 = OH, R.sub.4 = C(OCH.sub.2 CH.sub.2           O)CH.sub.3,                                                                   R.sub.5 = NHCH.sub.2 C.sub.6 H.sub.3 (OCH.sub.3).sub.2                   A36: 7-deoxy-7-(3',4'-dimethoxybenzylamino)-daunomycinone                          R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = COCH.sub.3,                                                                 R.sub.5 = NHCH.sub.2 C.sub.6 H.sub.3 (OCH.sub.3).sub.2                   A37: 7-deoxy-7-benzylamino-daunomycinone                                           R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = COCH.sub.3, R.sub.5 = NHCH.sub.2 C.sub.6 H.sub.5                       A38: 7-deoxy-7-(2'-hydroxyethylamino)-daunomycinone                                R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = COCH.sub.3, R.sub.5 = NHCH.sub.2 CH.sub.2 OH                           A39: 4-demethoxy-7-deoxy-7-(3',4'-dimethoxybenzylamino)-                           daunomycinone                                                                 R.sub.1 = R.sub.2 = H, R.sub.3 = OH, R.sub.4 = COCH.sub.3, R.sub.5 =          NHCH.sub.2 C.sub.6 H.sub.3 (OCH.sub.3).sub.2                             A40: 7-deoxy-7-amino-13-deoxo-13-ethylenedioxy-                                    daunomycinone                                                                 R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4                       = C(OCH.sub.2 CH.sub.2 O)CH.sub.3, R.sub.5 = NH.sub.2                    A41: 4-demethoxy-7-deoxy-7-amino-13-deoxo-13-                                      ethylenedioxy-daunomycinone                                                   R.sub.1 = R.sub.2 = H, R.sub.3 = OH, R.sub.4 = C(OCH.sub.2 CH.sub.2           O)CH.sub.3, R.sub.5 = NH.sub.2                                           A42: 7-deoxy-7-aminodaunomycinone                                                  R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = OH, R.sub.4 COCH.sub.3,           R.sub.5 = NH.sub.2                                                       A43: 4-demethoxy-7-deoxy-7-aminodaunomycinone                                      R.sub.1 = R.sub.2 = H, R.sub.3 = OH, R.sub.4 = COCH.sub.3, R.sub.5 =          NH.sub.2                                                                 A44: 13-deoxo-14-(N-morpholino)-daunomycinone                                       ##STR25##                                                               A45: 4-demethoxy-13-deoxo-14-(N-morpholino)-daunomycinone                           ##STR26##                                                               A46: 13-deoxo-14-aminoethyloxyethylamino-daunomycinone                             R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH,                     R.sub.4 = CH.sub.2 CH.sub.2 NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2              NH.sub.2                                                                 A47: 7-deoxy-14-O-(3'-amino-4'-methansulfonyl-2',3',4',6'-                         tetradeoxy-L-lyxohexopyranosyl)-daunomycinone                                 R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 = H, R.sub.3 = OH, R.sub.4 =           COCH.sub.2 R.sub.8 wherein R.sub.8 is a                                       group of formula B wherein R.sub.13 = H and R.sub.14 = OSO.sub.2              CH.sub.3                                                                 A48: 7-deoxy-14-O-(3'-amino-4'-iodo-2',3',4',6'                                    tetradeoxy-L-lyxohexopyransoyl)daunomycinone                                  R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 H, R.sub.3 = OH, R.sub.4 =             COCH.sub.2 R.sub.8 wherein R.sub.8 is a                                       group of formula B wherein R.sub.13 = H and R.sub.14 = I                 A49: 7-deoxo-14-O- 2'-(1"-piperazinyl)-                                            carbonyltetrahydropyran-6'-yl!-daunomycinone                                   ##STR27##                                                               A50: 14-(p-aminophenyloxy)-daunomycinone                                           R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.5 =           COCH.sub.2 OC.sub.6 H.sub.4 (pNH.sub.2)                                  A51: 14- p-(dimethylaminomethylcarbonylamino)                                      phenyloxy!daunomycinone                                                       R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH,                     R.sub.4 = COCH.sub.2 OC.sub.6 H.sub.4  pNHCOCH.sub.2 N(CH.sub.3).sub.         2 !                                                                      A52: 4-demethoxy-14-(p-aminophenyloxy)-daunomycinone                               R.sub.1 = R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.4 = COCH.sub.2           O.sub.6 H.sub.4 (p-NH.sub.2)                                             A53: 4-demethoxy-14- p-(dimethylaminomethylcarbonylamino)                          phenyloxy!-daunomycinone                                                      R.sub.1 = R.sub.2 = H, R.sub.3 = R.sub.5 = OH,                                R.sub.4 = COCH.sub.2 OC.sub.6 H.sub.4 (p-NHCOCH.sub.2 N(CH.sub.3).sub         .2 !                                                                     A54: 7-deoxy-14-(p-aminophenyloxy)-daunomycinone                                   R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                     R.sub.4 = COCH.sub.2 OC.sub.6 H.sub.4 (p-NH.sub.2)                       A55: 7-deoxy-14- p-(dimethylaminomethylcarbonylamino)                              phenyloxy!-daunomycinone                                                      R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                     R.sub.4 = COCH.sub.2 OC.sub.6 H.sub.4  p-NHCOCH.sub.2 N(CH.sub.3).sub         .2 !                                                                     A56: 7-deoxy-4-demethoxy-14-(p-aminophenyloxy)-daunomycinone                       R.sub.1 = R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                                R.sub.4 = COCH.sub.2 OC.sub.6 H.sub.4 (p-NH.sub.2)                       A57: 7-deoxy-4-demethoxy-14 p-(dimethylaminomethyl-                                carbonylaminomethyl)phenyloxy!-daunomycinone                                  R.sub.1 = R.sub.2 = R.sub.5 = H, R.sub.3 = OH,                                R.sub.4 = COCH.sub.2 OC.sub.6 H.sub.4  pNHCOCH.sub.2 N(CH.sub.3).sub.         2 !                                                                      A58: 14- N-diethylamino!-daunomucinone                                             R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.4 =           COCH.sub.2 N(C.sub.2 H.sub.5).sub.2                                      A59: 13-dihydro-14-(N-morpholino)-daunomycinone                                    R.sub.1 = OCH.sub.3, R.sub.2 = H, R.sub.3 = R.sub.5 = OH, R.sub.4 =           CHOHCH.sub.2 N(CH.sub.2).sub.2 O                                         A60: 7-deoxy-13-dihydro-14-(N-morpholino)-daunomycinone                            R.sub.1 = OCH.sub.3, R.sub.2 = R.sub.6 = H, R.sub.3 = OH, R.sub.4 =           CHOHCH.sub.2 N(CH.sub.2).sub.2 O                                         A61: 4-demethoxy-7-deoxy-10-hydroxy-14-(N-morpholino)-                             daunomycinone                                                                 R.sub.1 = R.sub.5 = H, R.sub.2 = OH, R.sub.4 = COCH.sub.2 N(CH.sub.2)         .sub.2 O                                                                 A62: 4-demethoxy-4-hydroxy-7-deoxy-7-(N-morpholino)                                daunomycinone                                                                 R.sub.1 = OH, R.sub.2 = H, R.sub.3 = OH, R.sub.4 = COCH.sub.3,                R.sub.5 = N(CH.sub.2).sub.2 O                                            A63: 4-demethoxy-7,9-dideoxy-14-(N-morpholino)-                                    daunomyucinone                                                           A64: 4-demethoxy, 4-hydroxy, 14-(N-morpholino)                                     daunomycinone                                                                 R.sub.1 = R.sub.3 = R.sub.5 = OH, R.sub.2 = H, R.sub.4 = COCH.sub.2           N(CH.sub.2).sub.2 O                                                      ______________________________________                                    

The compounds of formula A may be prepared, depending on the nature ofthe substituents, starting known anthracyclinones by appropriatechemical modifications. Processes for preparing compounds of formula Aand pharmaceutically acceptable salts thereof are as follows:

(i) A preferred process for the preparation of a compound of formula Awherein R₁ is OR₆ wherein R₆ is as above defined, R₂ is hydrogen orCOOCH₃, R₃ is OH, R₄ is C₁ or C₂ alkyl or COCH₃ and R₅ is hydrogen, OHor OCOOC₂ H₅, or a pharmaceutically acceptable salt thereof, comprises:

(1) protecting the 6-, 11- and, if present, 7-hydroxy groups of acompound of formula G ##STR28## wherein R_(b) represents hydrogen orCOOCH₃, R_(c) is C₁ or C₂ alkyl or COCH₃ and R_(e) is hydrogen orhydroxy, as a derivative of formula G1 ##STR29## wherein R_(b) and R_(c)are as previously defined and R'_(c) is hydrogen or the group OCOOC₂ H₅;

(2) demethylating such derivative of formula G1 and reacting theresulting 4-hydroxy compound of formula G2 ##STR30## wherein R_(b),R_(c) and R'_(e) are as defined above, with the appropriatehaloderivative of formula R₆ Hal, in which R₆ is as above defined andHal is halogen, preferably iodine;

(3) deblocking the 6- and 11-phenolic hydroxy groups of the resulting4-O-alkyl derivative, thus obtaining a compound of formula G3 ##STR31##wherein R₆, R_(b), R_(c) and R'_(e) are as above defined and, if desiredwhen R'_(e) is OCOOC₂ H₅, deblocking the 7-hydroxy group of compound G3;and

(4) if desired, converting the resulting said compound of formula A intoa pharmaceutically acceptable salt thereof.

(ii) In another example, a preferred process for the preparation of acompound of formula A wherein R₁ represents a group of formula OSO₂ R₇as above defined, R₂ is hydroxy or COOCH₃, R₃ is OH, R₄ is C₁ or C₂alkyl or COCH₃ and R₅ is hydrogen or hydroxy, or a pharmaceuticallyacceptable salt thereof, comprises treating an anthracyclinone offormula H ##STR32## wherein R_(b) is hydroxy or COOCH₃, R_(c) is C₁ orC₂ alkyl or COCH₃ and R_(e) is hydrogen or hydroxy, with the appropriatehaloderivative of formula HalSO₂ R₇ (Hal is halogen, preferably chlorineatom); and, if desired, converting the resulting said compound offormula A into a pharmaceutically acceptable salt thereof.

(iii) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₃ is OH, R₄ is COCH₃ and R₅ is a groupof formula N₉ R₁₀ wherein R₉ and R₁₀ are as above defined with provisothat R₉ or R₁₀ do not represent hydrogen or group of formula COR₁₁ orCOOR₁₁ as above defined, or a pharmaceutically acceptable salt thereof,comprises reacting an aglycone of formula K ##STR33## wherein R₁ and R₂are as previously defined, with the appropriate amine derivative offormula NHR₉ R₁₀, R₉ and R₁₀ are as above defined; and, if desired,converting the resulting said compound of formula A into apharmaceutically acceptable salt thereof.

(iv) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₃ is OH, R₄ is COCH₃ and R₅ is a groupof formula NR₉ R₁₀ wherein one of R₉ and R₁₀ is hydrogen atom and theother does not represent hydrogen or group of formula COR₁₁ or COOR₁₁,as above defined, or a pharmaceutically acceptable salt thereof,comprises:

(1) protecting an aglycone of formula K as above defined as a13-ethylenedioxy derivative of formula K1 ##STR34## wherein R₁ and R₂are as above defined; (2) reacting the said derivative of formula K1with the appropriate compound of formula NH₉ R₁₀, R₉ and R₁₀ are asabove defined;

(3) deblocking the 13-carbonyl group of the resulting7-amino-substituted derivative of formula K2 ##STR35## wherein R₁, R₂,R₉ and R₁₀, are as above defined; and, desired, converting the saidcompound of formula A into a pharmaceutically acceptable salt thereof,such as acidifying the compound A to obtain the acid addition salt.

(v) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₃ is OH, R₄ is COCH₃ and R₅ is NH₂, or apharmaceutically acceptable salt thereof, comprises:

(1) treating a derivative of formula K2, as above defined, in which NR₉R₁₀, represents 3',4',-dimethoxybenzylamino with an oxidising agent;

(2) deblocking the 13-carbonyl group from the resultant7-amino-substituted compound of formula K3 ##STR36## herein R₁ and R₂are as above defined; and (3) if desired, converting the resulting saidcompound of formula A into a pharmaceutically acceptable salt thereofsuch as acidifying the compound A to obtain the acid addition salt.

(vi) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₃ is OH or H, R₄ is COCH₂ NR₉ NR₁₀wherein R₉ and R₁₀ are as above defined with the proviso that they donot represent a group of formula COR₁₁ or COOR₁₁, and R₅ is hydrogen orOH, or a pharmaceutically acceptable salt thereof, comprises:

(1) converting a compound of formula L ##STR37## wherein R₁, R₂, R₃ andR_(e) are as above defined, into the corresponding 14-bromo derivativeof formula L1 ##STR38## wherein R₁, R₂, R₃ and R_(e) are as abovedefined; (2) reacting the 14-bromo derivative of formula L1 with theappropriate amine of formula NHR₉ R₁₀ wherein R₉ and R₁₀ are aspreviously defined with the proviso that they do not represent a groupof formula COR₁₁ or COOR₁₁ ; and

(3) if desired, converting the resulting said compound of formula A intoa pharmaceutically acceptable salt thereof such as acidifying thecompound A to obtain the acid addition salt.

(vii) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₄ is a group of formula COCH₂ O-Phwherein the phenyl (Ph) ring is optionally substituted by nitro, aminoor NR₉ ₁₀ as above defined, and R₅ is hydrogen or hydroxy, or apharmaceutically acceptable salt thereof, comprises

(1) reacting a compound of formula L1, as above defined, with a phenoloptionally substituted as defined above, preferably nitrophenol, in theform of a salt; and

(2) if desired, converting the resulting said compound of formula A intoa pharmaceutically acceptable salt thereof.

(viii) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₄ is a group of formula XCH₂ R₈ whereinR₈ represents a group of formula C and D as above defined, or apharmaceutically acceptable salt thereof, comprises reacting ananthracyclinone bearing a hydroxylated side chain at the 9-position,such as COCH₂ OH or CH₂ CH₂ OH, with a derivative of formula C' or D'##STR39## (2) if desired, hydrolysing the resulting ester derivative,thus obtaining anthracyclinones of formula A bearing a carboxy group onthe acetal moiety; and

(3) if desired, converting the resulting said compound of formula A intoa pharmaceutically acceptable salt thereof.

(ix) In another example, a preferred process for the preparation ofcompounds of formula A wherein R₄ is a group CH₂ CH₂ R₈, comprises:

(1) transforming a compound of formula A, as above defined, wherein R₄is a group of formula COCH₂ R₈ into the corresponding 13-hydrazonederivative, preferably a 13- (4-fluoro)benzenesulfonyl!hydrazone;

(2) reducing the above mentioned hydrazone derivative by using areducing agent in conditions capable of preserving the nature of thequinone system of the compound of formula A; and

(3) if desired, converting the resulting said compound of formula Awherein R₄ is a said group CH₂ CH₂ R₈ into a pharmaceutically acceptablesalt thereof.

It should be noted that, if desired, derivatives of formula A producedaccording to processes (i), (ii), (iii), (iv), (v), (vi), (vii), (viii)and (ix) can be further modified at different parts of the molecule bycombining processes above described or by means of synthetic proceduresdescribed for the anthracyclines or anthracyclinones (see: F. Arcamonein "Doxorubicin", Medicinal Chemistry Vol 17, Academic Press, 1981) orby means of general synthetic procedures (see: J. March, "AdvancedOrganic Reaction" Fourth Ed., J. Wiley & Sons, 1992). For example thecompounds of formula A wherein X is a CO group may be converted into acompound of formula A wherein X is CHOH by reduction, for example withsodium borohydride. A compound of formula A wherein R₅ is OH may beconverted into the corresponding compound having R₅ ═H by treatment withsodium dithionite.

The compounds of formula A as defined under (i) may be prepared asdescribed in DE-A-2,750,812, for example by reacting a compound offormula G as above defined with an excess of ethoxy-carbonyl chloride,in pyridine, at room temperature from 1 to 2 hours; then treating theprotected derivative G1 with aluminium bromide in dry aprotic solvent,preferably methylene chloride, at room temperature for 3 to 6 hours;alkylating the resulting 4-hydroxy derivative of formula G2 preferablywith a iodo-derivative of formula R₆ I, in aprotic solvent such asmethylene chloride or chloroform and in presence of a condensing agent,preferably silver oxide, at temperature from 40 to 60° C. for 6 to 24hours; then deblocking the hydroxy groups from compound of formula G3 byfirst eliminating the phenol protecting groups by treatment withmorpholine in polar protic solvent such as methanol, at roomtemperature, for from 1 to 3 hours, and then hydrolysing, if present,the 7-O-ethoxycarbonyl group with a very dilute solution of aqueoussodium hydroxide.

The compounds of formula A as defined under (ii) may be prepared asdescribed in U.S. Pat. No. 4,965,351, for example by dissolving acompound of formula H, as above defined, in a dry apolar solvent such asmethylene chloride and treating with a compound of formula HalSO₂ R₇ asabove defined (Hal is halogen), preferably chlorine, in presence of anorganic base such as N,N-diisopropylethylamine and a catalytic amount of4-dimethylamino pyridine, at a temperature from 0° to 30° C., preferablyat room temperature, from a few minutes to several hours.

The compounds of formula A as defined under (iii) may be prepared byreacting a compound of formula K as above defined with an aminoderivative of formula NHR₉ R₁₀ as above defined in a dry aprotic solventsuch as anhydrous methylene chloride, at a temperature from 10° to 30°C. for a few hours to several days; and, if desired, acidifying theresulting product, preferably with anhydrous hydrogen chloride inmethanol, to obtain the acid addition salt.

The compounds of formula A as defined under (iv) may be prepared byreacting a compound of formula K as above defined with ethylene glycolin toluene in presence of an acid catalyst, preferably p-toluensulfonicacid, at reflux temperature for 3 to 6 hours; then reacting theprotected derivative K1 with a compound of formula NHR₉ R₁₀ aspreviously defined in polar solvent such as pyridine ortetrahydrofurane, preferably at room temperature for one to severaldays; then deblocking the protected carbonyl group by treatingderivative of formula K2 with trifluoroacetic acid with few drops ofanisole, preferably at room temperature from 30 minutes to two hours;and, if desired, converting the resulting compound into an acid additionsalt, preferably with anhydrous hydrogen chloride in methanol.

The compounds of formula A as defined under (v) may be prepared, forexample, by reacting a compound of formula K2 as above defined in whichNR₉ R₁₀ represents the residue 3,4-dimethoxybenzylamino with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a mixture of waterand methylene chloride, at room temperature for one day; then deblockingthe resultant derivative of formula K3, as above defined, withtrifluoroacetic acid and anisole at room temperature for one hour; and,if desired, converting the resulting compound into an acid additionsalt, preferably with anhydrous hydrogen chloride in methanol.

The compounds of formula A as defined under (vi) may be prepared asdescribed in DE-A-2,557,537, for example by reacting a compound offormula L1, prepared from compound L according to DE-A-1,917,874, withthe appropriate amine of formula NHR₉ R₁₀ wherein R₉ and R₁₀ are aspreviously defined with proviso that R₉ and R₁₀ do not represent a groupof formula COR₁₁, or COOR₁₁ as above defined, in a dry polar solventsuch as acetone or dimethylformamide, at a temperature of from about 20°to 60° C., for from 4 to 24 hours, and, if desired, converting theresulting compound into an acid addition salt, preferably with anhydroushydrogen chloride in methanol.

The compounds of formula A as defined under (vii) may be prepared asdescribed in DE-A-1,917,874, for example by reacting a compound offormula L1, as above defined, with a phenol derivative as previouslydefined, in aprotic organic solvent such as acetone, in presence ofbase, preferably potassium or sodium carbonate at temperature from 20°to 60° C.

The compounds of formula A as defined under (viii) may be prepared asdescribed in WO 92/10212 and WO 92/02255, for example by reacting ananthracyclinone as above defined with derivatives of formula C' or D' inpresence of acid catalyst, for example pyridinium p-toluensulfonate inaprotic solvent such as methylene chloride at temperature from 10° to30° C., preferably room temperature and from 3 to 24 hours; and, ifdesired, hydrolysing the ester derivative with dilute aqueous sodiumhydroxide.

The compounds of formula A as defined under (ix) may be prepared asdescribed in GB-A-2238540, for example by reducing the 13-(4-fluoro)benzensulfonyl!hydrazone derivative of an anthracyclinone offormula A as above defined with sodium cyanoborohydride in organicsolvent, such as toluene or dimethylformamide, at temperature from 25°to 80° C., for 6 to 24 hours.

Some of the starting materials for the preparation of compounds offormula A are known. Others may be analogously prepared starting fromknown compounds by means of known procedures.

For example, the following compounds are known and can be represented bythe same formula A:

daunomycinone (R₁ ═OCH₃, R₂ ═H, R₃ ═R₅ ═OH, R₄ ═COCH₃),

adriamycinone (R₁ ═OCH₃, R₂ ═H, R₃ ═R₄ ═OH, R₅ ═COCH₂ OH), p14-demethoxydaunomycinone (R₁ ═R₂ ═H, R₃ ═R₅ ═OH, R₄ ═COCH₃),

carminomycinone: (R₂ ═OH, R₂ ═H, R₃ ═R₅ ═OH, R₄ ═COCH₃),

β-rhodomycinone (R₁ ═R₂ ═R₃ ═R₅ ═OH, R₄ ═CH₂ CH₃),

ε-rhodomycinone (R₁ ═R₃ ═R₅ ═OH, R₂ ═COOCH₃, R₄ ═CH₂ CH₃),

the corresponding 7-deoxy derivatives (R₅ ═H) (see: F. Arcamone in"Doxorubicin" Medicinal Chemistry, vol.17, Academic Press 1981) or thesugar derivatives of formula M ##STR40## such as the amino sugarsdaunosamine, 3-amino-2,3,6-trideoxy-L-lyxo-hexopyranose, (M1: R_(s)═NH₂, R_(t) ═R_(x) ═OH, R_(u) ═H) (see: J.Am.Chem.Soc., 86, 5334, 1964)or acosamine, 3-amino-2,3,6-trideoxy-L-arabino-hexopyranose, (M2: R_(s)═NH₂, R_(u) ═R_(x) ═OH, R_(t) ═H) (see: J. Med.Chem., 18, 703, 1975) orthe corresponding 1-chloro-3,4-di-trifluoroacetyl daunosaminylderivatives (R_(x) ═Cl and R₅ ═NHCOCF₃, R_(t) ═OCOCF₃) or1-chloro-3,4-ditrifluoroacetyl acosaminyl derivatives (R_(x) ═Cl andR_(s) ═NHCOCF₃, R_(u) ═OCOCF₃).

The compounds of the present invention are characterized by highinhibitory activity on amyloidosis.

The term amyloidosis indicates various diseases whose commoncharacteristic is the tendency of particular proteins to polymerize andprecipitate, as insoluble fibrils, into the extracellular space causingstructural and functional damage to organ and tissues. Theclassification of amyloid and amyloidosis has been recently revised inBulletin of the World Health Organisation 71(1): 105 (1993).

All the different types of amyloid share the same ultrastructuralorganization in anti-parallel β-pleated sheets despite the fact thatthey contain a variety of widely differing protein subunits see: GlennerG. G., New England J.Med. 302 (23): 1283 81980)!. AL amyloidosis iscaused by peculiar monoclonal immunoglobulin light chains which formamyloid fibrils. These monoclonal light chains are produced bymonoclonal plasma cells with a low mitotic index which accounts fortheir well known insensitivity to chemotherapy. The malignancy of thesecells consists in their protidosynthetic activity.

The clinical course of the disease depends on the selectivity of organinvolvement; the prognosis can be extremely unfavourable in case ofheart infiltration (median survival<12 months) or more benign in case ofkidney involvement (median survival approx. 5 years).

Considering the relative insensitivity of the amyloidogenic deposits toproteclytic digestion, a molecule that can block or slow amyloidformation and increase the solubility of existing amyloid deposits seemsthe only reasonable hope for patients with AL amyloidosis. Furthermore,since the supermolecular organization of the amyloid fibrils is the samefor all types of amyloid, the availability of a drug that interfereswith amyloid formation and increase the solubility of existing deposits,allowing clearance by normal mechanisms, could be of great benefit forall types of amyloidosis, and in particular for the treatment ofAlzheimer's disease.

Indeed, the major pathological feature of Alzheimer's Disease (AD), DownSyndrome, Dementia pugilistica and Cerebral amyloid angiopaty is amyloiddeposition in cerebral parenchyma and vessel walls. These markers areassociated with neuronal cell loss in cerebral cortex, limbic regionsand subcortical nuclei. Several studies have shown that selective damageto various neuronal systems and synapse loss in the frontal cortex hasbeen correlated with cognitive decline. The pathogenesis and molecularbasis of neurodegenerative processes in AD is not known, but the role ofβ-amyloid, deposited in brain parenchyma and vessel walls has beenhighlighted by recent report of its neurotoxic activity in vitro and invivo (Yanker et al. Science, 245: 417, 1990. Kowall et al. PNAS, 88:7247, 1991). Furthermore, the segregation of familiar AD with mutationof the amyloid precursor protein (APP) gene has aroused interest in thepotential pathogenetic function of β-amyloid in AD Mullan M. et al.TINS, 16(10): 392 (1993)!.

The neurotoxicity of β-amyloid has been associated with the fibrilogenicproperties of protein. Studies with homologous synthetic peptidesindicate that hippocampal cells were insensitive to exposure to freschβ1-42 solution for 24 h while their viability decreased when neuronswere exposed to β1-42 previously stored in saline solution for 2-4 daysat 37° C. to favour the peptide aggregation. The relationship betweenfibrils and neurotoxicity is further supported by recent evidenceshowing that the soluble form of β-amyloid is produced in vivo and invitro during normal cellular metabolism (Hass et al. Nature, 359, 322,1933) and only when it aggregate in congophilic formation was associatedwith distrophic nevrites. On the other hand, non-congophilic"preamyloid" formtion containing single molecule of β-amyloid was notassociated with neuronal alteration (Tagliavini et al. Neurosci.Lett.93: 191, 1988).

The neurotoxicity of β-amyloid has also been confirmed using a peptidehomologue β-amyloid fragment 25-35 (β25-35) reteining theself-aggregating properties of the complete β-amyloid fragment β142.

Chronic but not acute exposure of hippocampal neurons to micromolarconcentration of β25-35 induced neuronal death by the activation of amechanism of programmed cell death known as apoptosis (Forloni et al.NeuroReport, 4: 523, 1993). Here again, neurotoxicity was associatedwith the self aggregating propertiy of β25-35.

Other neurodegenerative disorder such as spongiform encephalopathy (SE)are characterized by neuronal death and extracellular deposition ofamyloid, in this case originated from Prion (PrP) protein. In analogywith the observation that β-amyloid is neurotoxic, the effects ofsynthetic peptides homologous to different segments of PrP on theviability of primary rat hippocampal neurons have been investigated. Thechronic application of peptide corresponding to PrP 106-126 inducedneuronal death by apoptosis while under the same conditions all theother peptides tested and the scrambled sequence of PrP 106-126 did notreduce cell viability (Forloni et al., Nature 362: 543). PrP 106-126resulted highly fibrilogenic in vitro and when stained with Congo red,the peptide aggregate showed green biifrangence indicative of theβ-sheets conformation characteristic of amyloid.

The compounds of the present invention can be used to make medicamentsuseful to prevent or arrest the progression of diseases caused byamyloid proteins, such as AL amyloidosis, Alzheimer's Disease or DownSyndrome and the like.

The present invention also includes, within its scope, pharmaceuticalcompositions comprising one or more compounds A as active ingredients,in association with pharmaceutically acceptable carriers, excipients orother additives, if necessary.

The pharmaceutical compositions containing a compound of formula A orsalts thereof may be prepared in a conventional way by employingconventional non-toxic pharmaceutical carriers or diluents in a varietyof dosage forms and ways of administration.

In particular, the compounds of the formula A can be administered:

A) orally, for example, as tablets, troches, lozenges, aqueous or oilysuspension, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known in the art for the manufactureof pharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavouring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, maize starch or alginic acid; binding agents, for examplemaize starch, gelatin or acacia, and lubrificating agents, for examplemagnesium stearate or stearic acid or talc. The tablets may be uncoatedor they may be coated by known techniques to delay disintegration andabsorpion in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed.Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phophate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, peanut oil, liquid paraffin or olive oil.Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions.

Such excipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be naturally-occurring phosphatides,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The said aqueous suspensions may also contain one or morepreservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavouring agents, or one or moresweetening agents, such as sucrose or saccharin. Oily suspension may beformulated by suspending the active ingredient in a vegetable oil, forexample arachis oil, olive oil, seseme oil or coconut oil or in amineral oil such as liquid paraffin. The oily suspensions may contain athickening agent, for example beewax, hard paraffin or cetyl alcohol.Sweetening agents, such as those set forth above, and flavoring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by the addition of an autoxidant such as ascorbic acid.Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixure with a dispersing or wetting agent, a suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and agents, mayalso be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil for example liquidparaffin or mixtures of these.

Suitable emulsifying agents may be naturally-occurring gums, for examplegum acacia or gum tragacanth, naturally-occurring phosphatides, forexample soy bean, lecithin, and esters or partial esters derived fromfatty acids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxyethylene sorbitan monooleate. The emulsion may alsocontain sweetening and flavoring agents. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, sorbitol orsucrose. Such formulations may also contain a demulcent, a preservativeand flavoring and coloring agents.

B) Parenterally, either subcutaneously or intravenously orintramuscularly, or intrasternally, or by infusion techniques, in theform of sterile injectable aqueous or olagenous suspension. Thepharmaceutical compositions may be in the form of a sterile injectableaqueous or olagenous suspensions.

These suspensions may be formulated according to the known art usingthose suitable dispersing of wetting agents and suspending agents whichhave been above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent for example, as a solution in1,3-butane diol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose any bland fixed oils may be conventionally employedincluding synthetic mono- or diglycerides. In addition fatty acids suchas oleic acid find use in the preparation of injectables;

Still a further object of the present invention is to provide a methodof controlling amyloidosis diseases by administering a therapeuticallyeffective amount of one or more of the active compounds encompassed bythe formula A in humans in need of such treatment.

Daily dose are in range of about 0.1 to about 50 mg per kg of bodyweight, according to the activity of the specific compound, the age,weight and conditions of the subject to be treated, the type and theseverity of the disease, and the frequency and route of administration;preferably, daily dosage levels are in the range of 5 mg to 2 g. Theamount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral may contain from 5 mg to 2 g of activeagent compounded with an appropriate and convenient amount of carriermaterial which may vary from about 5 to about 95 percent of the totalcomposition. Dosage unit forms will generally contain between from about5 mg to about 500 mg of the active ingredient.

The following Examples illustrate the invention without limiting it.

EXAMPLE 1 Preparation of 14-(N-morpholino)-daunomycinone (A1)

14-Bromodaunomycinone (L1': R₁ ═OCH₃, R₂ ═H, R₅ ═OH) (0.95 g, 2 mmol),prepared as described in J.Org.Chem., 42, 3653 (1977), was dissolved indry methylene chloride (50 ml), treated with morpholine (0.34 g, 4mmole) and kept at room temperature for 24 hours. After that, thesolvent was removed under reduced pressure and the crude product wasflash chromatographed on silicagel using a mixture of methylene chlorideand acetone (90:10 by volume) as eluent to give the title compound A1that was converted into the corresponding hydrochloride (0.8 g, yield77%) by addition of the stoichiometric amount of methanolic hydrogenchloride followed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/acetone(9:1 by volume), R_(f) =0.5

FD-MS: m/e 483 M!+

¹ HNMR (200 MHz, DMSO-D₆) δ: 2.03 (dd, J=4.5, 14.2 Hz, 1H, 8-ax); 2.32(d, J=14.2 Hz, 1H, H-8eq); 2.95 (d, J=18.5 Hz, 1H, H-10ax); 3.17 (d,J=18.5 Hz, 1H, H-10eq); 3.2,3.5 (m, 4H, --CH₂ --N--CH₂ --); 3.7,4.0 (m,4H, --CH₂ --O--CH₂ --); 4.02 (s, 3H, OCH₃); 4.87 (m, 2H, CH₂ -14); 5.16(m, 1H, H-7); 5.70 (broad signal, 1H, OH-7); 6.36 (s, 1H, OH-9); 7.68(m, 1H, H-3); 7.93 (m, 2H, H-1+H-2); 10.40 (broad signal, 1H, NH⁺);13.29 (s, 1H, OH-11); 14.01 (s, 1H, OH-6).

EXAMPLE 2 Preparation of 7-deoxy-7-(N-morpholino)-daunomycinone (A30)

7-Ethoxycarbonyl-daunomycinone (K': R₁ ═OCH₃, R₂ ═H) (0.94 g, 2 mmol)prepared as described in DE-A-2,750,812 was dissolved in a mixture ofmethylene chloride (50 ml) and methanol (5 ml), added with morpholine (3ml) and the mixture was kept at room temperature for 20 hours. Afterthat, the solvent was removed under reduced pressure and the crudematerial was flash chromatographed on silica gel using a mixture ofmethylene chloride and acetone (95:5 by volume) as eluting system togive the title compound A30 that was converted into the correspondinghydrochloride (0.5 g, yield 53%) by addition of the stoichiometricamount of methanolic hydrogen chloride followed by precipitation withethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/acetone(9:1 by volume), R_(f) =0.58

FD-MS: m/e 467 M!+

¹ HNMR (200 MHz, CDCl₁) δ: 1.77 (dd, J=3.3, 14.5 Hz, 1H, H-8ax); 2.32(dd, J=2.0, 14.5 Hz, 1H, H-8eq); 2.40 (s, 3H, COCH₃); 2.50,3.00 (m, 4H,--CH₂ 13 N--CH₂ --); 3.10,3.20 (Abq, J=18.7 Hz, 2H, CH₂ -10); 3.64 (m,4H, --CH₂ --O--CH₂ --); 4.08 (s, 3H, OCH₃); 4.35 (dd, J=2.0, 3.3 Hz, 1H,H-7); 7.38 (d, J=8.3 Hz, 1H, H-3); 7.78 (dd, J=7.7, 8.3 Hz, 1H, H-2);8.02 (d, J=7.7 Hz, 1H, H-1); 13.29 (s, 1H, OH-11); 14.11 (s, 1H, OH-6).

EXAMPLE 3 Preparation of7-deoxy-7-(3',4'-dimethoxybenzylamino)-13-deoxo-13-ethylenedioxy-daunomycinone(A32)

7-Ethoxycarbonyl-daunomycinone (K': 1.88 g, 4 mmol), prepared as abovedescribed, was disolved in toluene (100 ml), added with ethylene glycol(3 ml) and pyridinium p-toluen-sulfonate (0.1 g). The mixture wasrefluxed for 6 hours using a Dean-Stark apparatus to remove the water.After that, the reaction mixture was cooled at room temperature, washedwith aqueous 1% sodium hydrogen carbonate, and water. The organic phasewas dried over anhydrous sodium sulphate and the organic solvent removedunder reduced pressure to give 13-ethylendioxo derivative K' (0.92 g).

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/acetone(9:1 by volume), R_(f) =0.25

FD-MS: m/e 518 M!+

The 13-ethylendioxo derivative K' (0.85 g, 1.64 mmol) was dissolved in amixture of pyridine (20 ml) and dry tetrahydrofurane (20 ml), added with3,4-dimethoxy benzylamine (1 ml) and kept at room temperature for twodays. After that, the reaction mixture was diluted with methylenechloride (100 ml ) and washed with 1N aqueous hydrogen chloride, waterand 1% aqueous sodium hydrogen carbonate. The organic phase wasseparated and the solvent was removed under reduced pressure. The crudematerial was flash chromatographed on silica gel using a mixture ofmethylene chloride and acetone (95:5 by volume) as eluting system togive the title compound A32 that was converted into the correspondinghydrochloride by addition of the stoichiometric amount of methanolichydrogen chloride followed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/acetone(9:1 by volume), R_(f) =0.8

FD-MS: m/e 607 M!+

¹ HNMR (200 MHz, CDCl₃) δ: 1.49 (s, 3H, CH₃); 1.62 (dd, J=4.0, 14.2 Hz,1H, H-8ax); 2.45 (ddd, J=1.8, 1.8, 14.2 Hz, 1H, H-8eq); 2.86 (d, J=19.1Hz, 1H,H-10ax); 3.21 (dd, J=1.8, 19.1 Hz, 1H, H-10eq); 3.85, 3.88 (2×s,6H, OCH₃); 4.06 (s, 7H, 4-OCH₃ +--O--CH₂ --CH₂ --O--); 4.44 (dd,J=1.8,4.0 Hz, 1H, H-7); 6.8-6.9 (m, 3H, H-2'+H-5'+H-6'); 7.34 (dd, J=1.0, 8.5Hz, 1H, H-3); 7.75 (dd, J=7.8, 8.5 Hz, 1H, H-2); 8.01 (dd, J=10, 7.8 Hz,1H, H-1)

EXAMPLE 4 Preparation of7-deoxy-7-(3',4'-dimethoxybenzylamino)daunomycinone (A36)

Compound A32 (0.3 g) prepared as described in Example 3, was dissolvedin trifluoroacetic acid (3 ml) and added with one drop of anisole. Afterone hour the reaction mixture was diluted with methylene chloride,washed with 1% aqueous sodium hydrogen carbonate, dried over anhydroussodium sulphate. The organic solvent was removed under reduced pressureand the crude material was flash chromatographed on silicagel, using amixture of methylene chloride and methanol (95:5 by volume) as elutingsystem, to give 7-deoxy-7-(3',4'-dimethoxybenzylamino)daunomycinone(A36) that was converted into the corresponding hydrochloride byaddition of the stoichiometric amount of methanolic hydrogen chloridefollowed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (8:2 by volume), R_(f) 0.5

FD-MS: m/e 547 M!+

¹ HNMR (200 MHz, DMSO-D₆) δ: 2.02 (dd, J=5.0, 14.4 Hz, 1H, H-8ax); 2.34(s, 3H, COCH₃); 2.48 (m, 1H, H-8eq); 2.98,3.08 (Abq, J=19.0 Hz, 2H, CH₂-10); 3.74, 3.78 (2×s, 6H, OCH₃); 4.00 (s, 3H, 4-OCH₃); 4.35 (m, 2H,NH--CH₂ -aryl); 4.59 (m, 1H, H-7); 6.80 (broad signal, 1H, OH-9); 6.99(d, J=8.1 Hz, 1H, H-5'); 7.15 (d, J=8.1 Hz, 1H, H-6'); 7.31 (s, 1H,H-2'); 7.69 (m, 1H, H-3); 7.92 (m, 2H, H-1+H-2); 8.5,8.9 (broad signal,2H, NH₂ ⁺); 12.99 (broad signal, 1H, OH-11); 13.94 (broad signal, 1H,OH-6).

EXAMPLE 5 Preparation of7-deoxy-7-benzylamino-13-deoxo-13-ethylenedioxy-daunomycinone (A33)

13-Ethylendioxo derivative K1' (0.85 g, 1.64 mmol), prepared asdescribed in Example 3, was dissolved in a mixture of methylene chloride(40 ml) and methanol (4 ml), treated with benzylamine (0.5 ml) and keptat room temperature for 18 hours. After that, the solvent was removedunder reduced pressure and the crude material was flash chromatographedon silicagel using a mixture of methylene chloride and acetone (9:1 byvolume) as eluting system, to give the title compound A33 (0.55 g) thatwas converted into the corresponding hydrochloride by addition of thestoichiometric amount of methanolic hydrogen chloride followed byprecipitation with ethyl ether. TLC on Kieselgel F₂₅₄ (Merck), elutingsystem methylene chloride/acetone (9:1 by volume), R_(f) =0.20

EXAMPLE 6 Preparation of 7-deoxy-7-benzylamino-daunomycinone (A37)

Compound A33, prepared as described in Example 5, was treated withtrifluoroacetic as described in Example 4, to give7-deoxy-7-benzylamino-daunomycinone (A37) that was converted into thecorresponding hydrochloride by addition of the stoichiometric amount ofmethanolic hydrogen chloride followed by precipitation with ethyl ether.chloride/acetone (9:1 by volume), R_(f) =0.60

FD-MS: m/e 487 M!+

¹ HNMR (200 MHz, CDCl₃) δ: 1.76 (dd, J=4.1, 14.4 Hz, 1H, H-8ax); 2.33(ddd, J=1.7, 1.9, 14.4 Hz, 1H, H-8eq); 2.42 (s, 3H, COCH₃); 2.88 (d,J=18.8 Hz, 1H, H-10ax); 3.14 (dd, J=1.9, 18.8 Hz, 1H, H-10eq); 3.91,4.08(Abq, J=12.4 Hz, 2H, NH--CH₂ -aryl); 4.04 (s, 3H, 4-OCH₃); 4.41 (dd,J=1.7, 4.1 Hz, 1H, H-7); 7.3-7.4 (m, 6H, C₆ H₅ --+H-3); 7.72 (dd, J=7.8,8.5 Hz, 1H, H-2); 7.94 (dd, J=1.1, 7.8 Hz, 1H, H-1); 13.20 (broadsignal, 1H, OH-11) 13.40 (broad signal, 1H, OH-6).

EXAMPLE 7 Preparation of7-deoxy-7-(2'-hydroxyethylamino)-13-deoxo-13-ethylenedioxy-daunomycinone(A34)

The title compound A34 was prepared according to the procedure describedin Example 3, but using ethanolamine.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (9:1 by volume), R_(f) 0.2

¹ HNMR (200 MHz, CDCl₃) δ: 1.45 (s, 3H, CH₃); 1.57(dd, J=4.1, 14.1 Hz,1H, H-8ax); 2.37 (ddd, J=1.4, 1.4, 14.1 Hz, 1H, H-8eq); 2.80 (d, J=19.0Hz, 1H, H-10ax); 3.03 (m, 2H, NH--CH₂ --CH₂ --OH); 3.11 (dd, J=1.4, 19.0Hz, 1H, H-10eq); 3.6-4.0 (m, 2H, NH--CH₂ --CH₂ --OH); 3.99 (s, 3H,OCH₃); 4.04 (s, 4H, --O--CH₂ --CH₂ --O--); 4.34 (m, 1H, H-7); 7.29 (d,J=7.7 Hz, 1H, H-3); 7.69 (dd, J=7.7, 7.7 Hz, 1H, H-2); 7.88 (d, J=7.7Hz, 1H, H-1).

EXAMPLE 8 Preparation of 7-deoxy-7-(2'-hydroxyethylamino)-daunomycinone(A38)

The title compound A38 was prepared from compound A34 following theprocedure described in Example 4.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (9:1 by volume), R_(f) 0.5 FD-MS: m/e 441 M!+

¹ HNMR (200 MHz, CDCl₃) δ: 1.80 (dd, J=4.2, 14.4 Hz, 1H, H-8ax); 2.28(ddd, J=1.8, 2.0, 14.4 Hz, 1H, H-8eq); 2.41 (s, 3H, COCH₃); 2.96 (d,J=18.5 Hz, 1H, H-10ax); 3.03 (m, 2H, NH--CH₂ --CH₂ --OH); 3.20 (dd,J=1.8, 18.5 Hz, 1H, H-10eq); 3.5-4.0 (m, 2H, NH--CH₂ --CH₂ --OH); 4.08(s, 3H, OCH₃); 4.45 (dd, J=2.0, 4.2 Hz, 1H, H-7); 7.39 (J=1.0, 8.5 Hz,1H,H-3); 7.78 (J=7.7, 8.5 Hz, 1H, H-2); 8.03 (dd, J=1.0, 7.7 Hz, 1H,H-1).

EXAMPLE 9 Preparation of 7-deoxy-13-ethylenedioxy-7-amino-daunomycinone(A40)

7-deoxy-7-(3',4'-dimethoxybenzylamino)-13-deoxo-13-ethylenedioxy-daunomycinone(A32, 0.5 g), prepared as described in Example 3, was dissolved in amixture of methylene chloride (80 ml) and water (4 ml), added with2,3-dichloro-5,6-dicyano-1,4-benzo-quinone (DDQ) and kept at roomtemperature for 24 hours. Then the reaction mixture was washed with 1%aqueous sodium hydrogen carbonate. The organic phase was separated andthe solvent removed under reduced pressure to give the title compoundA40 (0.3 g).

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (6:1 by volume), R_(f) =0.25

EXAMPLE 10 Preparation of 7-deoxy-7-amino-daunomycinone (A42)

Compound A40 (0.2 g) prepared as described in Example 9, was treatedwith trifluoroacetic as described in Example 4, to give, after flashchromatography on silicagel using a mixture of methylene chloride andmethanol (95:5 by volume), 7-deoxy-7-aminodaunomycinone (A42, 0.14 g)that was converted in the corresponding chloridrate by addition of thestechiometric amount of methanolic hydrogen chloride followed byprecipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (6:1 by volume), R_(f) 0.33

FD-MS: m/e 397 M!+

¹ HNMR (200 MHz, DMSO-D₆) δ: 1.79 (dd, J=5.3, 14.9 Hz, 1H, H-8ax); 2.02(d, J=14.9 Hz, 1H,H-8eq); 2.29 (s, 3H, COCH₃); 2.76 (d, J=18.6 Hz, 1H,H-10ax); 2.89 (d, J=18.6 Hz, 1H, H-10eq); 3.96 (s, 3H, 4-OCH₃); 4.31 (d,J=5.3 Hz, 1H, H-7); 7.60 (m, 1H, H-1+H-2); 8.00 (broad signal, 2H, NH₂).

EXAMPLE 11 Preparation of 14-(N-piperidino)-daunomycinone (A2)

14-bromodaunomycinone (L1': R₁ ═OCH₃, R₂ ═H, R₅ ═OH) (0.95 g, 2 mmol),prepared as described in J. Org. Chem., 42, 3653 (1977) was dissolved indry methylene chloride (50 ml), trated with piperidine (0.34 g, 4 mmol)and kept at room temperature for 16 hours. The solvent was then removedunder reduced pressure and the crude product was flash chromatographedon silica gel eluting with a mixture of methylene chloride and methanol(96:4 by volume) to give the title compound that was converted into thecorresponding hydrochloride (0.55 g, yield 53%) by addition of thestoichiometric amount of methanolic hydrogen chloride followed byprecipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (9:1 by volume), R_(f) =0.5.

FAB-MS: m/e 482 M+H!⁺

¹ H-NMR (200 MHz, DMSO-D6) δ: 1.2-1.9 (m, 6H, piperidine CH₂ -3+CH₂-4+CH₂ -5); 1.97 (dd, J=4.6, 14.1 Hz, 1H, H-8ax); 2.30 (d, J=14.1 Hz,1H, H-8eq); 2.89 (d, J=18.4 Hz, 1H, H-10ax); 3.0, 3.4 (m, 4H, piperidineCH₂ -1+CH₂ -6); 3.13 (d, J=18.4 Hz, 1H, H-10eq); 3.97 (s, 3H, OCH₃ -4);4.76 (m, 2H, CH₂ -14); 5.10 (m, 1H, H-7); 5.60 (d, J=6.6 Hz, 1H, OH-7);6.39 (s, 1H, OH-9); 7.64 (m, 1H, H-3); 7.90 (m, 2H, H-1+H-2); 9.7 (broadsignal, 1H, HN⁺); 13.23 (s, 1H, OH-11); 13.95 (s, 1H, OH-6)

EXAMPLE 12 Preparation of 14- N-(N'-methyl)-piperazino!daunomycinone(A4)

The title compound was prepared analogously as described in examples 1and 2.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/methylalcohol (8:2 by volume), R_(f) =0.36.

FAB-MS: m/e=497 M+H!⁺

¹ H-NMR (200 MHz, CDCl₃) δ: 2.14 (dd, J=4.8, 14.5 Hz, 1H, H-8ax); 2.32(s, 3H, NCH₃); 2.36 (ddd, J=2.0, 2.0, 14.5 Hz, 1H, H-8eq); 2.4-2.7 (m,8H, piperazine hydrogens); 2.98 (d, J=18.5 Hz, 1H, H-10ax); 3.17 (dd,J=2.0, 18.5 Hz, 1H, H-10eq); 3.60, 3.72 (two doublets, J=16.7 Hz, 2H,CH₂ -14); 4.0 (broad signal, 1H, OH-7); 4.09 (s, 3H, OCH₃ -4); 5.27 (dd,J=2.0, 4.8 Hz, 1H, H-7); 6.1 (broad signal, 1H, OH-9); 7.39 (dd, J=1.1,8.6 Hz, 1H, H-3); 7.78 (dd, J=7.7, 8.6 Hz, 1H, H-2); 8.02 (dd, J=1.1,7.7 Hz, 1H, H-1); 13.31 (broad signal, 1H, OH-11); 13.97 (s, 1H, OH-6)

EXAMPLE 13 Preparation of 14- N-diethylamino!daunomycinone (A58)

The title compound was prepared analogously as described in examples 1and 2.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/methylalcohol (9:1 by volume), R_(f) =0.45.

FAB-MS: m/e=470 M+H!⁺

¹ H-NMR (200 MHz, CDCl₃) δ: 1.15 (t, J=7.2 Hz, 6H, N(CH₂ CH₃)₂); 2.14(dd, J=4.8, 14.5 Hz, 1H, H-8ax); 2.37 (ddd, J=2.0, 2.0, 14.5 Hz, 1H,H-8eq); 2.69 (m, 4H, N(CH₂ CH₃)₂); 2.97 (d, J=18.5 Hz, 1H, H-10ax); 3.21(dd, J=2.0, 18.5 Hz, 1H, H-10eq); 3.58, 3.73 (two doublets, J=15.4 Hz,2H, CH₂ -14); 4.08 (s, 3H, OCH₃ -4); 5.23 (dd, J=2.0, 4.8 Hz, 1H, H-7);7.38 (dd, J=1.0, 8.3 Hz, 1H, H-3); 7.76 (dd, J=7.7, 8.3 Hz, 1H, H-2);8.02 (dd, J=1.0, 7.7 Hz, 1H, H-1); 13.3 (broad signal, 1H, OH-11); 14.0(broad signal, 1H, OH-6)

EXAMPLE 14 Preparation of 4-demethoxy-14-(N-morpholino)-daunomycinone(A10)

The title compound was prepared as reported in example 1 starting from4-demethoxy-14-bromodaunomycinone, which was obtained by bromination of4-demethoxy-daunomycinone according to the procedure described in J.Org. Chem., 4.2, 3653 (1977) for daunomycinone.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/methylalcohol (96:4 by volume), R_(f) =0.21.

FAB-MS: m/e 454 M+H!⁺

¹ H-NMR (200 MHz, DMSO-D6) δ: 1.96 (dd, J=4.6, 14.3 Hz, 1H, H-8ax); 2.16(dd, J=2.0, 14.3 Hz, 1H, H-8eq); 2.44 (m, 4H, N(CH₂ CH₂)₂ O); 2.92, 3.00(two doublets, J=18.7 Hz, 2H, CH₂ -10); 3.57 (m, 4H, N(CH₂ CH₂)₂O);3.67, 3.72 (two doublets, J=18.9 Hz, 2H, CH₂ -14); 5.03 (m, 1H, H-7);5.4 (broad signal, 1H, OH-7); 6.05 (s, 1H, OH-9); 7.96 (m, 2H, H-2+H-3);8.26 (m, 2H, H-1+H-4); 13.3 (broad signal, 2H, OH-6+OH-11)

EXAMPLE 15 Preparation of 4-demethoxy-7-deoxy-14-(N-morpholino)-daunomycinone (A24)

The title compound was prepared as reported in example 1 starting from4-demethoxy-7-deoxy-14-bromodaunomycinone, which was obtained bybromination of 4-demethoxy-7-deoxy-daunomycinone according to theprocedure described in J. Org. Chem., 42, 3653 (1977) for daunomycinone.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/methylalcohol (96:4 by volume), R_(f) =0.33.

FAB-MS: m/e 438 M+H!⁺

1H-NMR (200 MHz, CDCl₃) δ: 1.9-2.0 (m, 2H CH₂ -8);2.63 (m, 4H, N(CH₂CH₂)₂ O); 2.8-3.2 (m, 4H, CH₂ -7+CH₂ -10);3.46, 3.60 (two doublets,J=15.0 Hz, 2H, CH₂ -14); 3.78 (m, 4H, N(CH₂ CH₂)₂ O); 7.82 (m, 2H,H-2+H-3);8.32 (m, 2H, H-1+H-4); 13.44, 13.46 (two singlets, OH-6+OH-11)

EXAMPLE 16 preparation of 7-deoxy-14-(N-morpholino)-daunomycinone (A17)

A mixture of 14-(N-morpholino)-daunomycinone (A1) (1.5 g, 3.3 mmol) and5% palladium on activated carbon (300 mg) in 50 ml of dioxan was shakenunder a hydrogen pressure of 2 atm for one hour. The catalist was thenfiltered, the solvent evaporated under reduced pressure, and the residuepurified by column chromatography on silica gel (eluent methylenechloride/methyl alcohol 96:4 by volume). The title compound was isolated(0.4 g 28%) as a red powder that was converted into the correspondinghydrochloride by addition of the stoichiometric amount of methanolichydrogen chloride followed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylene chloride/methylalcohol (96:4 by volume), R_(f) =0.20.

FAB-MS: m/e 468 M+H!⁺

¹ H-NMR (200 MHz, DMSO-D6) δ: 1.7-2.2 (m, 2H CH₂ -8);2.83 (m, 2H CH₂-7); 2.91 (m, 2H CH₂ -10); 3.3, 3.8 (m, 8H, morpholine hydrogens); 3.97(s, 3H, OCH₃ -4); 4.8 (m, 2H, CH₂ -14); 6.14 (broad signal, OH-9); 7.65(m, 1H, H-3); 7.91 (m, 2H, H-1+H-2); 10.4 (broad signal, 1H, HN⁺); 13.34(s, 1H, OH-11); 13.85 (s, 1H, OH-6)

EXAMPLE 17 Preparation of 13-dihydro-14-(N-morpholino)-daunomycinone(A59)

Magnesium bromide ethyl etherate (2.24 g, 8.68 mmoles) was addeddropwise to a stirred suspension of 14-(N-morpholino)-daunomycinone (A1)(2.10 g, 4.34 mmol) in tetrahydrofuran (80 ml) under argon atmosphere.To the resulting mixture, cooled at -40° C., sodium borohydride (0.164g, 4.34 mmol) was added portionwise. After stirring at -40° C. for 1.5hours the reaction was quenched by dropwise addition of methyl alcohol(25 ml). Volatilies were evaporated under reduced pressure and theresidue was purified by column chromatography on silica gel (eluentchloroform/methyl alcohol 94:6 by volume). The title compound wasisolated (1.39 g 66%) as a red powder that was converted into thecorresponding hydrochloride by addition of the stoichiometric amount ofmethanolic hydrogen chloride followed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system chloroform/methyl alcohol(94:6 by volume), R_(f) =0.30.

FAB-MS: m/e 486 M+H!⁺

¹ H-NMR (200 MHz, DMSO-D6) δ: 1.7-2.2 (m, 2H CH₂ -8); 2.3-2.8 (m, 6H,CH₂ -14+N(CH₂ CH₂)₂ O); 2.86 (m, 2H CH₂ -10); 3.57 (m, 5H, N(CH₂ CH₂)₂O+CH-13); 3.97 (s, 3H, OCH₃ -4); 4.81 (d, J=5.5 Hz, 1H, OH-13); 5.03 (m,1H, H-7); 5.20 (m, 1H, OH-7); 5.6, 5.8 (broad signal, 1H, OH-9); 7.5-8.0(m, 3H, H-1+H-2+H-3); 13.3 (broad signal, 1H, OH-11); 13.9 (broadsignal, 1H, OH-6)

EXAMPLE 18 Preparation of7-deoxy-13-dihydro-14-(N-morpholino)-daunomycinone (A60)

A solution of sodium dithionite (2.15 g, 1.23 mmol) in water (8 ml) wasadded dropwise to a stirred solution of13-dihydro-14-(N-morpholino)-daunomycinone (0.240 g, 0.494mmol),prepared as described in the previous example, indimethylformamide (16 ml) at room temperature under argon atmosphere.After stirring 1 hour at room temperature, the reaction mixture waspoured into water (250 ml) and extracted with ethyl acetate (6×25 ml).The layers were separated, the organic layer was washed with water,dried over sodium sulphate and evaporated to give 300 mg of rawmaterial, which was purified by column chromatography on silica gel(eluent chloroform/methyl alcohol 96:4 by volume). The title compoundwas isolated (116 mg, 50%) as a red powder that was converted into thecorresponding hydrochloride by addition of the stoichiometric amount ofmethanolic hydrogen chloride followed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system chloroform/methyl alcohol(96:4 by volume), R_(f) =0.20.

FAB-MS: m/e 470 M+H!⁺

¹ H-NMR (400 MHz, DMSO-D6) δ: 1.56 (m, 1H, H-8ax); 1.82 (m, 1H, H-8eq);2.38 (dd, J=7.7, 12.8 Hz, 1H, CH(H)-14); 2.63 (dd, J=3.7, 12.8 Hz, 1H,CH(H)-14); 2.45 (m, 4H, N(CH₂ CH₂)₂ O); 2.6-2.9 (m, 4H, CH₂ -10+CH₂ -7);3.53 (m, 4H, N(CH₂ CH₂)₂ O); 3.53 (m, 1H, CH-13); 3.94 (s, 3H, OCH₃ -4);4.65 (d, J=5.1, Hz, 1H, OH-13); 4.76 (broad signal, 1H, OH-9); 7.58 (m,1H, H-3); 7.86 (m, 2H, H-1+H-2); 13.36 (s, 1H, OH-11); 13.88 (s, 1H,OH-6);

EXAMPLE 19 Preparation of4-demethoxy-7-deoxy-10-hydroxy-14-(N-morpholino)-daunomycinone (A61)

A solution of ruthenium trichloride hydrate (27 mg, 0.1 mmol) and sodiumperiodate (0.48 g, 2.2 mmol) in water (3 ml) was added dropwise to astirred suspension of 4-demethoxy-7-deoxy-9,10-anhydro-daunomycinone,prepared as described in J. Org: Chem., 48, 2820 (1983), (0.5 g, 1.5mmol) in ethyl acetate/acetonitrile 1:1 (20 ml) at 0° C. under argonatmosphere. After stirring 0.5 hour at 0° C., the reaction mixture waspoured into an aqueous solution of sodium thiosulphate (20 ml) andextracted with methylene chloride. The layers were separated, theorganic layer was washed with water, dried over sodium sulphate andevaporated to give 300 mg of raw material, which was purified by columnchromatography over silica gel (eluent chloroform/methyl alcohol 50:0.2by volume). 4-Demethoxy-7-deoxy-10-hydroxy-daunomycinone was isolated(194 mg, 35%) as a red powder, m.p. 241°-242° C. (dec.).

4-Demethoxy-7-deoxy-10-hydroxy-14-bromodaunomycinone was prepared from4-demethoxy-7-deoxy-10-hydroxy-daunomycinone following the brominationprocedure described in J.Org.Chem. 42, 3653, (1977) for daunomycinone.Red powder; m.p. 223°-225° C. (dec.)

According to the procedure outlined in example 1,4-demethoxy-7-deoxy-10-hydrxy-14-bromodaunomycinone was converted to thetitle compound, which was isolated as a red powder that was convertedinto the corresponding hydrochloride by addition of the stoichiometricamount of methanolic hydrogen chloride followed by precipitation withethyl ether.

TLC on Kiesenlgel F₂₅₄ (Merck), eluting system chloroform/methyl alcohol(96:4 by volume), R_(f) =0.30.

FAB-MS: m/e 453 M+H!⁺

¹ H-NMR (200 MHz, DMSO-D6) δ: 1.8-3.0 (m, 4H, CH₂ -8+CH₂ -7); 2.36 (m,4H, N(CH₂ CH₂)₂ O); 3.47 (m, 4H, N(CH₂ CH₂)₂ O); 3.59 (s, 2H, CH₂ -14);4.90 (s, 1H, H-10); 5.60 (broad signals, 1H, OH-10); 5.67 (s, 1H, H-9);7.94 (m, 2H, H-2+H-3); 8.27 (m, 2H, H-1+H-4); 13.30 (broad signals, 2H,OH-6+OH-11);

EXAMPLE 20 Preparation of4-demethoxy-4-hydroxy-7-deoxy-7-(N-morpholino)daunomycinone (A 62)

4-demethoxy, 4-hydroxy, O⁶,O⁷ -diethoxyycarbonyldaunomycinone (1.3 g,2.5 mmol), prepared from 6,7,11 triethoxycarbonyldaunomycinone (G1:R_(b) ═H, R_(c) ═COCH₃, R'_(e) ═OCOOC₂ H₅) as described in I1 Farmaco,Ed. Sc., 35, 347 (1980), was dissolved in a mixture of methylenechloride (40 ml) and methanol (40 ml) and 1 ml of morpholine was added.The mixture was kept at room temperature for 20 hours. The solvent wasremoved under reduced pressure and the crude material was flashchromatographed on silica gel using a mixture of methylene chloride andacetone (9:1 by volume) as eluting system to give the title compoundthat was converted into the corresponding hydrochloride (0.3 g, yield25%) by addition of the stoichiometric amount of methanolic hydrogenchloride followed by precipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (9:1 by volume), R_(f) =0.8

FAB-MS: m/e 502 M+H!⁺

¹ H-NMR (200 MHz, DMSO-D6) δ: 1.85 (m, 1H, H-8ax);2.10 (m, 1H, OCH₂CH(Hax)N);2.20 (m, 1H, H-8eq); 2.32 (d, J=10.7 Hz, 1H, CH(H)-14); 2.40(m, 2H, NCH₂ CH₂ OH); 2.68 (m, 1H, OCH₂ CH(Heq)N); 2.77, 2.86 (d, J=19.2Hz, 1H, H-10ax);2.83 (d, J=10.7 Hz, 1H, CH(H)-14); 3.07, 3.10 (d, J=19.2Hz, 1H, H-10eq);3.47 (m, 2H, NCH₂ CH₂ OH);3.57 (m, 1H, NCH₂ CH(Hax)O);3.90 (m, 1H, NCH₂ CH(Heq)O);3.97 (s, 3H, OCH₃ -4);4.40 (m, 1H, CH₂ OH);5.00 (m, 1H, H-7); 5.23 (d, J=7.7 Hz, 1H, OH-7);5.32, 5.34, 5.84, 5.93(s, 2H, OH-9+OH-13);7.63 (m, 1H, H-3);7.87 (m, 2H, H-1+H-2);13.31 (broadsignal, 1H, OH-11); 13.97 (broad signal, 1H, OH-6)

EXAMPLE 21 Preparation of4-demethoxy-7,9-dideoxy-14-(N-morpholino)-daunomycinone (A 63)

4-Demethoxy-7,9-dideoxy-14-bromodaunomycinone was prepared from4-demethoxy-7,9-dideoxy-10-hydroxy-daunomycinone, prepared as describedin Synt. Commun.,15, 1081 (1985), following the bromination proceduredescribed in J.Org.Chem. 42, 3653, (1977) for daunomycinone.

According to the procedure outlined in example1,4-demethoxy-7,9-dideoxy-14-bromodaunomycinone was converted to thetitle compound, which was isolated as a red powder that was convertedinto the corresponding hydrochloride by addition of the stoichiometricamount of methanolic hydrogen chloride followed by precipitation withethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system chloroform/methyl alcohol(98:2 by volume), R_(f) =0.23.

FAB-MS: m/e 422 M+H!⁺

¹ H-NMR (200 MHz, pyridine-d5) δ: 1.78 (m, 1H, H-8ax);2.18 (m, 1H,H-8eq);2.54 (m, 4H, N(CH₂ CH₂)₂ O);2.70 (m, 1H, H-9); 2.9-3.3 (m, 4H,CH₂ -10+CH₂ -7);3.43 (m, 2H CH₂ -14);3.78 (m, 4H, N(CH₂ CH2)₂ O);7.75(m, 2H, H-2+H-3);8.39 (m, 2H, H-1+H-4);13.80 (broad signal, 2H,OH-6+OH-11)

EXAMPLE 22 Preparation of 4-demethoxy, 4-hydroxy,14-(N-morpholino)daunomycinone (A 64)

A suspension of 4-demethoxy, 4-hydroxydaunomycinone (1.4 g, 3.6 mmol),prepared as described in J. Antibiotics, 31, 178 (1978), in 20 ml ofdioxane was treated with 10.3 ml of a bromine solution obtained bydiluting 1 ml of bromine up to 50 ml with dioxane. The reaction mixturewas stirred at room temperature during three hours and the resulting4-demethoxy, 4-hydroxy, 14-bromodaunomycinone was precipitated byaddition of 50 ml of petroleum ether. The precipitate was filtered,washed with petroleum ether and dried under vacuum to give 1.35 g (80%yield) of crude product that was used as such for the next reaction. Asuspension of 0.75 g (1.6 mmol) of 4-demethoxy, 4-hydroxy,14-bromo-daunomycinone in 50 ml of methylene chloride was treated with0.28 g (3.2 mmol) of morpholine and the resulting mixture was stirred atroom temperature during 24 hours. The solvent was then removed underreduced pressure and the crude product was flash chromatographed onsilica gel eluting with a mixture of methylene chloride and methanol(95:5 by volume) to give the title compound that was converted into thecorresponding hydrochloride (0.16 g, yield 20%) by addition of thestoichiometric amount of methanolic hydrogen chloride followed byprecipitation with ethyl ether.

TLC on Kieselgel F₂₅₄ (Merck), eluting system methylenechloride/methanol (9:1 by volume), R_(f) =0.6.

FAB-MS: m/e 470 M+H!⁺

¹ H-NMR (400 MHz, DMSO-D6) δ: 2.01 (dd, J=4.7, 14.1 Hz, 1H, H-8ax); 2.31(dd, J=14.1 Hz, 1H, H-8eq); 2.92, 3.16 (two doublets, J=18.8 Hz, 2H, CH₂-10); 3.1-3-3 (m, 4H, N(CH₂ CH₂)₂ O); 3.7-4.0 (m, 4H, N(CH₂ CH₂)₂ O);4.80, 4.87 (two doublets, J=18.8 Hz, 2H, CH₂ -14); 5.11 (m, 1H, H-7);5.70 (broad signals, 1H, OH-7); 6.34 (s, 1H, OH-9); 7.41 (m, 1H, H-3);7.8-7.9 (m, 2H, H-1+H-2); 10.40 (broad signal 1H, HN⁺); 11.98 (s, 1HOH-4); 12.80 (s, 1H, OH-6); 13.40 (s, 1H, OH-11);

Biological test

Anthracyclinone derivatives of formula A interfere with theself-aggregating activity of β-amyloid fragment 25-35 and PrP fragment106-126 by using light scattering analysis.

β25-35 (GSNKGAIIGLH) and PrP 106-126 (KTNMKHMAGAAAAGAVVGGLG) weresynthesized using solid phase chemistry by a 430A Applied BiosystemsInstruments and purified by reverse-phase HPLC (Beckman Inst. mod 243)according to Forloni et al., Nature 362: 543, 1993. Light scattering ofthe peptide solutions was evaluated by spectrofluorimetriy (Perkin ElmerLS 50B), excitation and emission were monitored at 600 nm. β-amyloidfragment 25-35 and PrP 106-126 were dissolved at a concentration of 0.5to 1 mg/ml (0.4-0.8 mM and 0.2-0.4 mM respectively) in a solution ofphosphate buffer pH 5, 10 mM spontaneously aggregate within an hour.

The tested compounds, dissolved at several concentration (0.2-2 mM) inTris buffer 5 mM pH 7.4, were added to the peptidic solutions at themoment of their preparation in order to evaluate the process offibrilogenesis. The compounds prepared in examples 1-22, added atequimolar concentration with β-amyloid fragment 25-35 and PrP 106-126,showed complete prevention of the agregation.

Neurotoxicity.

Neuronal cells were obtained from the cerebral cortex of foetal rats atembryonic day 17 and cultured in the presence of foetal calf serum (10%)as described by Forloni et al., (Mol.Brain.Res. 16: 128, 1992).

The intrinsic cytotoxicity of compounds A has been evaluated by therepeated exposure of the cortical neurons to different concentration ofthe compounds ranging from the nanomolar to the micromolarconcentrations.

Neuronal cell death has been quantifyied by a colorimetric methoddescribed by Mossmann et al., (J.immunol.Meth., 65, 55-63, 1983).

Up to concentration of 10 μM all the tested compounds were devoided ofany neurotoxic effect.

We claim:
 1. A method of treating amyloidosis, comprising administeringan effective amount of an anthracyclinone of formula A to a patient inneed thereof: ##STR41## wherein R₁ represents: hydrogen or hydroxy;agroup of formula OR₆ in which R₆ is C₁ -C₆ alkyl, C₅₋₆ cycloalkyl or CH₂Ph with the phenyl (Ph) ring optionally substituted by 1, 2 or 3substituents selected from F, Cl, Br,C₁ -C₆ -alkyl, C₁ -C₆ alkoxy andCF₃ ; R₂ represents hydrogen, hydroxy, or OR₆ wherein R₆ is as abovedefined; R₃ represents hydrogen, hydroxy, or OR₆ as above defined; R₄represents a group of formula XCH₂ R₈ in which X is CO and R₈ is:a groupof formula NR₉ R₁₀ in which: R₉ and R₁₀ are each independently selectedfrom:(a) hydrogen, (b) a C₁ -C₆ alkyl or C₂ -C₆ alkenyl group optionallysubstituted with hydroxy, CN, COR₁₁, COOR₁₁, CONR₁₁ R₁₂, O(CH₂),_(n)NR₁₁ R₁₂ (n is 2 to 4) or N₁₁ R₁₂ in which R₁₁ and R₁₂ are eachindependently selected from hydrogen, a C₁ -C₁₂ alkyl or C₂ -C₁₂ alkenylgroup or phenyl optionally substituted by one or more substituentsselected from C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃, OH, NH₂ orCN, (c) C₃₋₆ cycloalkyl optionally substituted with COR₁₁, COOR₁₁ or OHwherein R₁₁ is as above defined, (d) phenyl (C₁ -C₄ alkyl or C₂ -C₄alkenyl) optionally substituted on the phenyl ring by one or moresubstituents selected from C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃,OH, NH₂ or CN, or (e) COR₁₁, COOR₁₁, CONR₁₁ R₁₂, COCH₂ NR₁₁ R₁₂, CONR₁₁COOR₁₂ or SO₂ R₁₂ in which R₁₁ and R₁₂ are as above defined, or R₉ andR₁₀ together with the nitrogen atom to which they are attached form:(f)A morpholino ring optionally substituted with C₁ -C₄ alkyl or C₁ -C₄alkoxy, (g) a piperazino ring optionally substituted by C₁ -C₆ alkyl, C₂-C₆ alkenyl or phenyl optionally substituted by one or more substituentsselected from C₁ -C₆ alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃, OH, NH₂ orCN, or (h) a pyrrolidino, piperidino or tetrahydropyridino ringoptionally substituted by OH, NH₂, COOH, COOR₁₁ or CONR₁₁ R₁₂ whereinR₁₁ and R₁₂ are as above defined, C₁ -C₆ alkyl, C₂ -C₆ alkenyl or phenyloptionally substituted by one of more substituents selected from C₁ -C₆alkyl, C₁ -C₆ alkoxy, F, Br, Cl, CF₃, OH, NH₂ or CN; R₅ representshydrogen, hydroxy a group of formula OR₆ wherein R₆ is as abovedefined;or a pharmaceutically acceptable salt thereof.
 2. The methodaccording to claim 1 wherein R₁ is hydrogen or methoxy.
 3. The methodaccording to claim 1 wherein R₂ is hydrogen.
 4. The method according toclaim 1 wherein R₃ is hydroxy.
 5. The method according to claim 1wherein R₄ is a group of formula XCH₂ R₈ in which X is CO and R₈ is agroup of formula NR₉ R₁₀, wherein R₉ and R₁₀ are each independentlyselected from:(a') hydrogen, (b') C₁ -C₄ alkyl optionally substituted byO(CH₂)_(n) NR₁₁ R₁₂ or NR₁₁ R₁₂, (d') benzyl optionally substituted onthe phenyl ring by one of more substituents selected from C_(1-C) ₄alkyl, C₁ -C₄ alkoxy, F, Br, Cl, CF₃, OH, NH₂ or CN, or (e') COCF₃ orCOCH₂ NR₁₁ R₁₂ wherein R₁₁ and R₁₂ are as above defined, or R₉ and R₁₀together with the nitrogen atom to which they are attached form: (f) amorpholino ring, (g') a piperazino ring optionally substituted by C₁ -C₄alkyl, or (h') a pyrrolidino, piperidino, or tetrahydropyridino ring. 6.The method according to claim 5 wherein R₄ is a group of formula XCH₂ R₈wherein X is CO and R₈ is a group of formula NR₉ R₁₀, wherein R₉ and R₁₀are each independently selected from:(a") hydrogen, (b") a methyl orethyl group optionally substituted by O(CH₂)_(n) NH₂ or NH₂ wherein n isas above defined, (d") benzyl optionally substituted on the phenyl ringby 1, 2 or 3 substituents selected from the group consisting of C_(1-C)₄ alkyl and C₁ -C₄ alkoxy, or (e") COCF₃ or COCH₂ N(C₁ -C₄ alkyl)₂, orR₉ and R₁₀ together with the nitrogen atom to which they are attachedform: (f") a morpholino ring, (g") a piperazino ring optionallysubstituted by C₁ -C₄ alkyl, or (h") a pyrrolidino, piperidino or1,2,3,6 tetrahydropyridino ring.
 7. The method according to claim 1wherein R₅ is hydrogen or hydroxy.
 8. The method according to claim 1wherein the patient has AL amyloidosis, Alzheimer's disease or Down'ssyndrome.
 9. The method according to claim 1 wherein the anthracyclinoneis administered in a dosage unit form containing from 5 to 500 mg of thecompound of formula A or pharmaceutically acceptable salt thereof. 10.The method of claim 1, whereinR₁ ═OCH₃, R₂ ═H, R₃ ═R₅ ═OH, and ##STR42##